Hypothalamic Peptides in the Control of Alcohol Intake

下丘脑肽控制酒精摄入量

• 批准号: 8577115
• 负责人: SARAH F LEIBOWITZ
• 金额: $ 36.88万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577115
• 关键词: Adolescent; Adult; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Aminobutyric Acids; Animals; Antibodies; Area; Arousal; Back; Behavioral; Biological; Birth; Blood; Brain; Breeding; Cell Proliferation; Chronic; Clinical; Consumption; Development; Dopamine; Drug Design; Eating; Effectiveness; Embryonic Development; Enkephalins; Ethanol; Exhibits; Exposure to; Feedback; Feeds; Figs - dietary; Galanin; Gene Expression; Glutamates; Heavy Drinking; Human; Hypothalamic structure; Ingestion; Label; Lateral; Learning; Life; Lobe; Measures; Mediating; Medicine; Microdialysis; Neuroepithelial; Neurons; Neuropeptides; Neurotransmitters; Oral; Pattern; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Process; Rattus; Regulation; Relapse; Rewards; Risk; Role; Signal Transduction; Site; Specific qualifier value; Sprague-Dawley Rats; System; Techniques; Testing; Third ventricle structure; Training; Work; alcohol exposure; alcohol use disorder; alcohol use initiation; alcoholism therapy; base; cell type; drinking; drinking behavior; fetal programming; gamma-Aminobutyric Acid; hypocretin; in utero; in vivo; melanin-concentrating hormone; mesolimbic system; neurochemistry; neurogenesis; neuromechanism; neurotransmitter release; novel; offspring; paraventricular nucleus; prenatal; prenatal exposure; prepuberty; prevent; programs; public health relevance; research study; response

DESCRIPTION (provided by applicant): Hypothalamic systems known to have a primary role in food intake are also important in controlling the consumption of ethanol. Our previous studies have shown that peptide systems in the hypothalamic paraventricular nucleus (PVN) become engaged in stimulating ethanol intake, which in turn feeds back to further increase the expression of these same peptides. More recently, we have begun to examine the perifornical lateral hypothalamus (PFLH) and have identified marked differences from the PVN in the functioning of the peptides in this area as they relate to ethanol consumption. Building on this information and the extensive preliminary results developed from it, we plan to test in Sprague-Dawley rats the novel idea that hypothalamic peptides expressed in the PFLH, specifically orexin (OX) and melanin-concentrating hormone (MCH), have different functions from those in the PVN, enkephalin (ENK) and galanin (GAL), in enhancing ethanol drinking. Whereas PFLH peptides initiate episodes of ethanol intake, PVN peptides prolong periods of ethanol consumption. Aim 1 is to examine the behavioral functions of these peptides in the PFLH and PVN, as they trigger or sustain ethanol intake, interact in this process, and respond in turn to the changes in ethanol consumption and corresponding blood ethanol concentrations. Aim 2 is to determine whether these peptides are disturbed in animals predicted to be at risk for overconsuming ethanol based on different behavioral- and bio-markers. We will test the hypothesis that animals at risk have disturbed expression of peptides in the hypothalamus prior to learning to drink ethanol or before an anticipated, large bout of ethanol consumption. This aim will also examine ENK in the mesolimbic dopamine (DA) system, which is intimately involved in controlling the ingestion of rewarding substances. Aim 3 is to determine whether animals at risk for overconsuming ethanol, due to prenatal exposure, exhibit disturbances in in utero development of these peptide systems that cause increased expression of the peptides and long-term overconsumption in the offspring. Lastly, Aim 4 is to investigate the hypothesis that neurochemical feedback signals to the PFLH compared to the PVN, via DA, -aminobutyric acid (GABA), glutamate (GLUT) and ENK inputs, have opposite effects on the local peptide systems that determine how they influence ethanol drinking behavior. As pharmacological therapies used to treat alcoholism act in part through these neurochemical control systems, we will test whether medications more effective in treating relapse in humans, seen as analogous to initiation of drinking, are working through the PFLH peptide systems; in contrast, those therapies more effective in treating ongoing excessive consumption, analogous to prolongation of drinking, are working through the PVN peptide systems. Collectively, these 4 Aims will provide significant, new information regarding the involvement and regulation of two hypothalamic areas and their local peptide systems, as they control patterns of ethanol drinking, contribute to alcohol abuse, and mediate the actions of medications in treating relapse and ongoing drinking in humans.

描述（由申请人提供）：已知在食物摄入中起主要作用的下丘脑系统在控制乙醇消耗方面也很重要。我们之前的研究表明，下丘脑室旁核（PVN）中的肽系统参与刺激乙醇摄入，反过来又进一步增加这些相同肽的表达。最近，我们开始检查下丘脑外侧角周围 (PFLH)，并发现该区域的肽功能与 PVN 存在显着差异，因为它们与乙醇消耗有关。基于这些信息和由此产生的广泛初步结果，我们计划在 Sprague-Dawley 大鼠中测试以下新观点：PFLH 中表达的下丘脑肽，特别是食欲素 (OX) 和黑色素浓缩激素 (MCH)，具有不同的功能来自 PVN、脑啡肽 (ENK) 和甘丙肽 (GAL) 的物质，可增强乙醇饮用量。 PFLH 肽会引发乙醇摄入，而 PVN 肽会延长乙醇消耗时间。目标 1 是检查 PFLH 和 PVN 中这些肽的行为功能，因为它们触发或维持乙醇摄入，在此过程中相互作用，并依次对乙醇消耗和相应血液乙醇浓度的变化做出反应。目标 2 是根据不同的行为和生物标志物，确定这些肽在预测有过度消耗乙醇风险的动物中是否受到干扰。我们将检验以下假设：处于危险中的动物在学习饮用乙醇之前或在预期的大量乙醇消耗之前已经扰乱了下丘脑中肽的表达。该目标还将检查中脑边缘多巴胺 (DA) 系统中的 ENK，该系统与控制奖励物质的摄入密切相关。目标 3 是确定由于产前暴露而面临过度消耗乙醇风险的动物是否会表现出这些肽系统的子宫内发育紊乱，从而导致肽表达增加和后代长期过度消耗。最后，目标 4 是研究以下假设：与 PVN 相比，通过 DA、γ-氨基丁酸 (GABA)、谷氨酸 (GLUT) 和 ENK 输入向 PFLH 发出的神经化学反馈信号对局部肽系统具有相反的影响，从而决定如何它们影响乙醇的饮用行为。由于用于治疗酗酒的药物疗法部分通过这些神经化学控制系统发挥作用，因此我们将测试是否可以通过 PFLH 肽系统更有效地治疗人类复发（被视为类似于开始饮酒）的药物；相比之下，那些治疗持续过度饮酒（类似于延长饮酒时间）更有效的疗法是通过 PVN 肽系统发挥作用的。总的来说，这 4 个目标将提供关于两个下丘脑区域及其局部肽系统的参与和调节的重要的新信息，因为它们控制乙醇饮用模式，导致酒精滥用，并介导治疗复发和持续性药物的作用。人类饮酒。